Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of cell subpopulations. They are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 12 million new cancer cases diagnosed and 7 million cancer deaths occurring each year. The National Cancer Institute estimates that greater than half a million Americans will die of cancer in 2013, accounting for nearly one out of every four deaths in the country. As the elderly population has grown, the incidence of cancer has concurrently risen, as the probability of developing cancer is more than two-fold higher after the age of seventy. Cancer care thus represents a significant and ever-increasing societal burden.
CD79b is the signaling component of the B-cell receptor and acts as a covalent heterodimer containing CD79a (i.e., Igα or mb-1) and CD79b (i.e., Igβ or B29). CD79b contains an extracellular immunoglobulin (Ig) domain, a transmembrane domain, and an intracellular signaling domain, an immunoreceptor tyrosine-based activation motif (ITAM) domain. By using flow cytometry, surface expression of CD79b has been detected in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) patients. Dornan et al., Blood 114(13):2721-9 (2009). In addition to its signaling functions, when the B-cell receptor is cross-linked, it is targeted to the major histocompatibility complex class II compartment, a lysosome-like compartment, as part of class II antigen presentation by B cells.
This feature of CD79b biology makes it a particularly attractive target for the use of ADCs because antibodies against CD79b are internalized and delivered to these lysosomal compartments, which are known to contain protease that can release the cytotoxic drug. Therefore, antibody-drug conjugates (ADC) have been generated (such as the humanized anti-CD79b antibody (humanized SN8) conjugated to monomethylauristatin E (MMAE) by a protease cleavable linker), which has shown to be clinical efficacious for the treatment of NHL. See e.g., U.S. Pat. No. 8,088,378 and Morschhauser et al., “4457 Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma” 56th ASH Annual Meeting and Exposition: Dec. 6-9, 2014. Despite the advances in NHL and CLL treatment using anti-CD79b ADC therapeutics, there still remains an unmet need for improved therapies for NHL and CLL patients, in particular those resistant to anti-CD79b ADC therapies.
Recently, bispecific antibody-based immunotherapies have been developed, which are capable of simultaneously binding cell surface antigens on cytotoxic cells and tumor cells with the intent that the bound cytotoxic cell will destroy the bound tumor cell. Such bispecific antibodies may have advantages, e.g., efficacy and/or safety compared to the antibody-drug conjugate. Thus, there is an unmet need in the field for the development of effective bispecific antibodies for use in cancer treatment.